Colon cancer Study Results Antibody pretargeting is a novel strategy to enhance tumor-selective delivery of toxic agents by administering an antibody conjugate to target tumors, and then administering a toxic agent such as a radioisotope which selectively binds to the conjugate. We conducted a phase II multi-center study to evaluate the efficacy and safety of such an approach in patients with advanced colorectal carcinoma (CRC). 25 patients (13 male, 12 female) with metastatic CRC were enrolled, median age 55 (range 37-74). Tumors were pretargeted through administration of murine monoclonal antibody NR-LU-10/streptavidin conjugate, dosed to 125 mg/ml of patient plasma volume. 48 hours later biotin-galactose-human serum albumin clearing agent was given to bind circulating antibody through streptavidin-biotin interactions for clearance by the reticuloendothelial system. 24 hours after the clearing agent, a single 110 mCi/m2 dose of biotinylated 90 Yttrium-DOTA was administered by intravenous bolus injection to target tumor sites through streptavidin-biotin binding with NR-LU-10. Two patients (8%) had a >80% decrease in the sum of the products of sentinel lesion diameters. One grade 5 toxicity was seen due to severe diarrhea, inducing hypokalemia, which potentially contributed to a fatal cardiac arrythmia in a patient with underlying coronary artery disease. The most common grade 3-4 toxicities were diarrhea (28%), thrombocytopenia (28%), anemia (16%), neutropenia (16%), fatigue (16%), and hypokalemia (12%). The targeted toxicity of diarrhea was probably related to expression of gp40, the NR-LU-10 target, on normal colon. Pancytopenia resulted from non-targeted toxicity from circulating radioisotope, as NR-LU-10 does not bind to bone marrow cells. This study demonstrates that a pretargeting approach can deliver therapeutic doses of radioisotopes to tumor in some cases. While the degree of response to a single dose of 90Yttrium-DOTA in patients with advanced, refractory disease is modest, the significant toxicities seen in this study warrantt additional refinement of the pretargeting strategy. Prostate Cancer Study Results. The utility of radiolabeled monoclonal antibodies has been limited by inadequate localization of antibody in tumor sites, and the presence of non-specific binding, resulting in a narrow therapeutic index. In order to address this problem, 14 patients with HRPC were treated with PRit. Patients were pretreated with NR-LU-10, a pan-carcinoma specific antibody, linked to streptavidin. Forty-eight hours later any remaining (free) circulating antibody was cleared with biotinylated human albumin. All patients had their serum assayed for free antibody prior to receiving subsequent therapy. Twenty-four hours after the clearing agent, Yttrium-90-DOTA conjugated to biotin was administered in order to deliver a radiation dose to tumor-bound antibody. Two of 14 (14%) patients had a durable > 50% decline in PSA. Symptomatic improvement was observed in a majority of patients with pain. Toxicity was moderate, with grade > diarrhea occurring in 28% of patients, grade 4 neutropenia in 15%, and transient thrombocytopenia in 38%. The median time to Plt nadir was 5 weeks, and to ANC nadir 6.5 weeks. Human anti-mouse antibody and human anti-streptavidin antibody formation was universal. We conclude that PRit is feasible in patients with HPRC, and is able to safely deliver large doses of radiation targeted to tumor sites. This approach appears to have modest anti-HPRC activity, and future work will need to address anti-mouse and anti-streptavidin antibody formation.